神經(jīng)阻滯鎮(zhèn)痛術

1、Analgesics,Zhang, Bin,,pain,a. Acute pain (sharp pain)b. Chronic pain (dull pain),Pain transmission pathway,Noxious stimuli,,Primary afferent fibres,nociceptor,Spinal cord,Limbic system,,,Somato-sensory cortex,mood eff

2、ect, the affective aspect of pain,the sensory aspect of pain,Dorsal horn,,,,Drug treatment of pain,cholinoceptor-blocking drugs,vasodilator drugs (eg. Nitroglycerin),Carbamazepine,Local anaesthetics,Cortex,Spinal c

3、ord,Dorsal horn,,,,,PGs,K+、H＋,BK,5-HT,NSAIDs,,Opioids,Sites of action of different drugs,opioid analgesics(narcotic analgesic, addictive analgesics),,,Opium (阿片) is the dried exudate obtained from unripe seedpods of the

4、 poppy Papaver somniferum, containing morphine, codeine, and other alkaloid substances.,Opiate (阿片劑) means that a substance is extracted from opium or is similar in structure to natural substances present in opium.,Opioi

5、d (阿片樣物質) is a term that designates substances that are not derived from opium. It refers particularly to opioid peptides, i.e. endogenous compounds that bind to opioid receptors and mimic the effect of morphine-like com

6、pounds.,Widely use term,Opium,The flower of papaver,Opium (阿片),Opiate (阿片劑),MorphineCodeinePapaverine (罌粟堿) … …,,structure-activity relationship,,,海洛因,嗎啡,納洛酮,,,,,,,Opioid (阿片樣物質),Endogenous opioid peptides:,Enkep

7、halins,,Endorphins,Dynorphins,Orphanin,,,,1992~,1973,,1962,1975,,analgesic site is laminae III of periventricular and periaqueductal gray area,,,,,,,,,put forward “receptors” for opiate analgesics in brain,isolated the

8、 first “endogenous opioid peptide” and named enkephalin,Cloned opioid receptors: μ κ δ ?,,,,Research history,Opioid receptors,G protein-coupled receptors,,?,?,?,?,Opioid receptors,supraspinal analgesia, sedation, euphor

9、ia, dependence, respiratory depression, miosis,spinal analgesia, sedation,dysphoria (煩躁不安), hallucination,spinal analgesia, sedation, euphoria, dependence, respiratory depression,,?:,?:,?:,?:,Spinal cord,Dorsal horn,,,,

10、,,enkephalins,Ca2+,Ca2+,Presynaptic terminal,Postsynaptic neuron,enkephalins,The cellular mechanisms,,,,,enkephalins,Presynaptic terminal,Postsynaptic neuron,The cellular mechanisms,,,,Morphine + receptors,,,,Open K+chan

11、nel,Close Ca2+channel,,抑制沖動傳導,,Ach, NA, Glu, 5-HT, P release ?,presynaptic,postsynaptic,Excitability ?,,The cellular mechanisms,The cellular mechanisms,Presynaptic inhibition: activation of opioid receptors on presynapti

12、c nerve terminals. Close Ca2+ channel, decrease Ca2+ input, and thereby reduce transmitter release (Ach, NA, Glu, 5-HT, P).Postsynaptic inhibition: activation of postsynaptic opioid receptors. Open K+ channels on postsy

13、naptic neurons, increase K+ output , and thereby cause hyperpolarization and thus reduce postsynaptic neuronal excitability.,,,Descending pain inhibitory pathways,Local inhibitory interneuron in spinal cord,Ascending pai

14、n transmission pathways,,,,Endogenous opioid peptides,,Pharmacological actions,CNS Smooth muscles3. Cardiovascular system,1.CNS effects: principal effects Analgesia Sedation & euphoria Respiratory depression C

15、ough suppression Others: miosis, nausea, hormone,(1) Analgesia insensitive: muscle spasms pain, deafferentation pain partially sensitive: nerve pain, CNS compression injury, bone cancer sensitive: myocardial infarct

16、ion, other types of cancers relieve anxiety and distress, tolerance of pain,1. CNS,灼性神經(jīng)痛(causalgia)系指在明確的神經(jīng)損傷后，與損傷神經(jīng)支配范圍相一致的區(qū)域內出現(xiàn)的以劇烈灼樣疼痛主要癥狀，表現(xiàn)為痛覺異常、痛覺過敏、交感神經(jīng)機能障礙、血流障礙、出汗異常、骨、肌肉萎縮，有時表現(xiàn)出水腫性改變的慢性頑固性疼痛綜合征。,(2) Sed

17、ation and euphoria,,drowsiness and clouding of mentation,sleep induced and aroused easily,Euphoria,,a sense of contentment and well-being,,,Sedation:,,the main reason for drug abuse,Site: limbic system and locus ce

18、ruleus,respiratory rate ，tidal volume the most common cause of death from acute poisoning influenced by stimulusMechanisms: ? the sensitivity of respiratory center to increased CO2 tension,(3) Respiratory

19、 depression,,,,(4) Cough suppression,antitussive effect by inhibiting cough center,codeine,(5) Other CNS effects,Miosis: pinpoint pupilsNausea and vomiting: CTZ ? muscular tension:限制 胸廓活動,影響呼吸Hormone: ↓ LH ,FSH, ↑

20、prolactin, GH, ADH,2. Smooth muscle system Gastrointestinal system Biliary tract Urinary system genital system,,(1) Gastrointestinal tract,,delays passage,,,secretion of digestive gland,indigesti

21、on,,,central inhibition,a call of nature defecation reflex,,,,,GIT tone,,GIT motility,,,,absorption of water,,,,biliary colic,constrict biliary smooth muscle constrict Oddi's sphincter,pressure in the bi

22、liary tract,(2) Biliary tract,,,,(3) Urinary tract,constrict ureteral smooth muscle bladder sphincter tone,urinary retention,uterine tone?,prolong labor,,,,,(4) Genital tract,,orthostatic hypotension,Mecha

23、nisms: release of histamine vasomotor center,3. Cardiovascular system,(1),,peripheral arterial and venous dilatation,,,,(2) intracranial pressure,,secondary to respiratory depression,Cl

24、inical uses,AnalgesiaCardiac asthmaAntidiarrheaAntitussiveCombined anesthesia,Analgesia terminal cancer myocardial infarction renal and biliary colic (atropine) trauma, burn, operation,at regular time and qua

25、ntity,,,,,Pulmonary edema,dyspnea,Acute left ventricular dysfunction,short of breath (respiratory center),CO2 retention,anxiety and distress,,Alveolar hypoventilation,,,,,,Cardiac asthma and morphine therapy,2. C

26、ardiac asthma,,,oxygen consumption,,(1) Mechanisms:① peripheral arterial and venous dilation preload and afterload pulmonary edema② sedation anxiety and distress

27、 oxygen consumption ③ the sensitivity of respiratory center to CO2 shortness of breath,,,Cardiac asthma,,,,,,,,,,Opioid analgesic drugs,Morphine (嗎啡)Heroin (海

28、洛因，二醋嗎啡)Codeine (可待因) Pethidine (哌替啶) Methadone (美沙酮)Fentanyl (芬太尼)buprenorphine (丁丙諾啡)Tramadol (曲馬多),Morphine,1803 Serturner isolated a pure active alkaline substance from opium. He proposed the name “morphine”

29、 for it after Morpheus.,,absorption,excretion,distribution,,free drug,blood,liver,iv.,Bioavailability25-30%,metabolism,美施康定（硫酸嗎啡緩釋片） 1. 強效，作用持續(xù)12 hr。主要用于晚期癌癥患者第三階梯止痛。 2. 抑制呼吸，可引起惡心、嘔吐、便秘及排尿困難，長期應用可產(chǎn)生耐受性、身體依賴

30、性和成癮性。,Heroin (diamorphine),Semisynthetic substance, prodrug of morphineMore lipid soluble than morphineMore rapid onset,德國拜爾公司 heroin在德文中意為英雄萬能藥 藥品轉變?yōu)槎酒?白粉,Codeine,higher oral efficacy2. lower efficacy than

31、 morphine3. use as antitussive, severe dry cough. 聯(lián)邦止咳露 ：麻黃堿+可待因+氯苯那敏+氯化銨,注意事項,不宜用于痰多粘稠者。連續(xù)應用不宜?2周，因久用可成癮。?7歲兒童禁用。,Pethidine (dolantin),Weaker potency than Morphine, no antitussive actionMore rapid onset and s

32、horter duration (2-4h) than morphineMetabolite: normeperidine ? convulsion Lyticcocktail,Methadone,1. synthetic compound, equal analgesia to morphine 2. milder abstinence syndrome 3. routinely used in detoxifi

33、cation of morphine addicts,Fentanyl,1. more analgesic potentcy than morphine:2. rapid onset and short duration of action 3. fentanyl, alfentanil, remifentanil: adjunctive drug for general anaesthesia 4. Fentanyl +

34、Droperidol (氟哌利多): neuroleptanalgesia (神經(jīng)阻滯鎮(zhèn)痛術),Used for minor surgery,5. breakthrough cancer pain:,口腔經(jīng)粘膜芬太尼拘櫞酸鹽(Oral Transmucosal Fentanyl Citrate, OTFC),Fentanyl lollipop,ACTIQ,芬太尼口腔粘膜貼片(Fentanyl sublingual tablets

35、),ABSTRAL,芬太尼透皮貼劑(Fentanyl transdermal system),多瑞吉,high lipid- soluble,Pentazocine,κ, ? agonist , μ partial agonist,increase blood pressure and cause tachycardia (? NA),weak action on μ : little addictive liabil

36、ity precipitate withdrawal syndrome of morphine abuser,列入非麻醉藥品。但久用仍會成癮！,analgesia and respiratory depression : weaker,Tramadol,Atypical opioid: weak μ activation, also interacts with monoaminergic systems (inhibit N

37、A and 5-HT reuptake)Alternative to traditional opioid analgesics,2008年1月1日國家將曲馬多列為精神藥品進行管理,延胡索乙素和羅通定,羅通定為左旋體的延胡索乙素，是有效部分。鎮(zhèn)靜安定鎮(zhèn)痛和中樞性肌肉松弛作用解熱鎮(zhèn)痛抗炎藥＜鎮(zhèn)痛作用＜哌替啶，鎮(zhèn)痛作用與阿片受體及前列腺素均無關無明顯成癮性口服后10-30min起效，維持2-5h，對慢性持續(xù)性鈍痛效果好不影響產(chǎn)程

38、,1. Tolerance,Adverse effects,large doses at short intervals readily cross tolerance full agonist: more obvious,2. Dependence,physical dependence： withdrawal syndrome psychological denpendence:

39、 compulsive drug- seeking behavior,Adverse effects,身體依賴性,精神依賴性,,,渴求,戒斷綜合征,強迫性用藥,依賴性,,,,藥物濫用,藥物濫用（drug abuse）: 非醫(yī)療目的反復使用具有依賴性潛能的精神活性物質。體驗該物質產(chǎn)生的特殊精神效應。,藥物誤用(drug misuse)：用藥適應證選擇不當 / 用量過大、療程過長等錯誤用藥行為。,,Withdrawalsyndro

40、me of Opioid,3. General adverse effects,4. Acute Morphine Poisoning,Naloxone,1. competitive full antagonist for opioid R (μ) 2. opioid overdose: reverses coma and respiratory depression 3. differential diagnosis in

41、morphine abuser : precipitates withdrawal symptom 4. short t1/2 (1h) , repeated injections,Contraindications,obstetric labor, breasting period obstructive airway disease, bronchial asthma head injuries serio

42、usly impaired hepatic or renal function,聯(lián)合國禁毒機構估計全球約2億人在濫用四類毒品，占全球15~64歲人口的5%。 阿片類 苯丙胺類 大麻 可卡因,Mode of administration of opioids,Oral administrationSublingual administrationRectal administrationIntravenous adm

43、inistrationIntramuscular administrationIntrathecal and epidural administration (鞘內給藥) (硬膜外給藥)Transdermal patch administration (透皮貼劑),Patient Controlled Analgesia (病人自控鎮(zhèn)痛，PCA),根據(jù)病人對鎮(zhèn)痛藥需求的個體差

44、異，使用專門設計的具有安全控制系統(tǒng)的微電腦輸液泵，由醫(yī)生設定給藥劑量，病人可以根據(jù)個人需要，通過按壓給藥按扭自行給藥，以滿足鎮(zhèn)痛治療個體化需要。術后鎮(zhèn)痛很多采取這種方法。醫(yī)生會根據(jù)您的情況設置一個安全劑量范圍，不必擔心按壓次數(shù)過多而引起藥物過量。,Non-opioid for mild pain,Pain persisting or increasing,Weak Opioids for moderate pain,Pain pers

45、isting or increasing,Strong Opioids for severe pain,,Freedom from cancer pain,NSAIDs e.g. aspirin, acetaminophen,e.g. codeine， tramadol,e.g. morphine, fentanyl, methadone,WHO analgesic ladder,Three steps